ABSTRACT Despite major efforts by the research community, effective therapies for Alzheimer's disease (AD) remain elusive. This indicates that innovative approaches are required and targeting aging is one such approach. Aging is a major risk factor for AD and dementia; yet, it is often overlooked. Studying biological mechanisms and populations that delay aging may lead to the identification of molecular factors that can protect from AD. Substantial evidence exists from our group and others that diminished signaling via the somatotropic pathway that signals via insulin-like growth factor-I delays aging, resulting in longer lifespan and dementia-free survival, not only in model organisms, but also in humans. In fact, centenarians, who are resilient to dementia despite advanced chronological age, are enriched with mutations that attenuate somatotropic signaling. Cognitive resilience conferred by reduced somatotropic signaling may be mediated by autophagy. Reduction in somatotropic signaling has been shown to up-regulate autophagy, a cellular process that maintains homeostasis by clearing dysfunctional proteins and cellular debris. Age-related decline in autophagic activity has been observed in most tissues and implicated in neurodegenerative diseases, including AD, but centenarians maintain their autophagic activity. This project brings together a multidisciplinary team of experts who will test the hypothesis that reduced somatotropic signaling results in cognitive resilience and protection from AD, in part, via enhanced autophagic activity. It will determine whether trajectories of somototropic hormones predict cognitive resilience and can be used as biomarkers (Aim 1). It will also apply to whole exome DNA sequence (WES) data novel computational methods that integrate functional genetic variants within genes that regulate the somatotropic axis with biological interactions between these genes on a pathway level to compute a genetic pathway score that estimates somatotropic function, as measured levels of circulating somatotropic hormones do not always reflect pathway function accurately. This genetic pathway score will subsequently be tested for its association with cognitive decline, AD incidence, brain imaging on MRI (Aim 2) and autophagic activity (Aim 3). These approaches will be applied to a longitudinal cohort of older adults (n=1,400; mean age 76, median follow-up 6.1 years) from the ongoing LonGenity study, who are annually evaluated with neurocognitive tests, have banked longitudinal biological samples, and have had WES. This unique cohort is (1) enriched with protective genes, as half of them are offspring of centenarians and is (2) relatively homogeneous genetically, as all subjects are from an Ashkenazi Jewish founder population, a feature that increases the power for genetic discovery. The project has the potential to discover genetic and molecular biomarkers for cognitive resilience. Moreover, it will thoroughly characterize the role of somatotropic signaling in the brain in aging humans and may identify mechanisms that confer cognitive resilience by delaying aging, which can be therapeutically targeted.